Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Ther Drug Monit. 2011 Dec;33(6):663-72. doi: 10.1097/FTD.0b013e31823415cc.
Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology.
The predictive capacity of 2 previously developed population pharmacokinetic models of tacrolimus in pediatric liver transplant recipients was tested in 20 new patients using Bayesian forecasting. Predictive performance was poor in the immediate posttransplant period with tacrolimus pharmacokinetics changing rapidly. A new population pharmacokinetic model, focusing on the immediate posttransplant period, was subsequently developed in 73 patients.
An increase in the apparent clearance of tacrolimus in the first few weeks after transplant was evident. Typical apparent clearance of tacrolimus was 0.148 L·h(-1)·kg(-0.75) immediately after transplantation, increasing to a maximum of 1.37 L·h(-1)·kg(-0.75). Typical apparent distribution volume was 27.2 L/kg. Internal and external validation studies confirmed the predictive capabilities of the developed model. Simulation studies reveal that in 60% of subjects the current initial standard dose without subsequent dosage adjustments overshoot the desired trough concentration range of 10-20 ng/mL. An alternative dosing schedule was developed based on allometric scaling with an initial loading dose followed by a maintenance dose increasing with time.
A population pharmacokinetic model for tacrolimus was developed, to better describe the early posttransplantation phase. This model has the potential to aid therapeutic drug monitoring and was also used to suggest a revised dosing scheme in the intended population.
他克莫司是一种具有狭窄治疗窗的免疫抑制剂，其药代动力学具有很大的可变性。在小儿肝移植中获得足够的浓度是至关重要的，但在移植后即刻尤其困难。预测药代动力学模型可以为开发新的初始剂量方案和贝叶斯方法的治疗药物监测提供基础。
使用贝叶斯预测，在 20 名新患者中测试了之前开发的两种小儿肝移植受者他克莫司群体药代动力学模型的预测能力。在移植后即刻，他克莫司药代动力学迅速变化，模型的预测性能较差。随后在 73 名患者中开发了一个新的群体药代动力学模型，重点关注移植后即刻。
在移植后的前几周，他克莫司的表观清除率明显增加。典型的他克莫司表观清除率在移植后立即为 0.148 L·h(-1)·kg(-0.75)，最高增加到 1.37 L·h(-1)·kg(-0.75)。典型的表观分布容积为 27.2 L/kg。内部和外部验证研究证实了所开发模型的预测能力。模拟研究表明，在 60%的受试者中，当前不进行后续剂量调整的初始标准剂量超过了 10-20ng/ml 的目标谷浓度范围。根据比例缩放，开发了一种替代的给药方案，包括初始负荷剂量，随后是随时间增加的维持剂量。
开发了一种他克莫司群体药代动力学模型，以更好地描述移植后早期阶段。该模型有可能有助于治疗药物监测，也被用于建议在目标人群中修订的给药方案。
